JP2002020288A - Leukocytic infiltration inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain both a leukocyte infiltration inhibitor and an eosinophils infiltration inhibitor having a low side effect. SOLUTION: The leukocyte infiltration inhibitor and the eosinophils infiltration inhibitor comprise N-hydroxy-N-[6-(3-pyridylmethyl)-2H-1-benzopyran-3- ylmethyl]urea (compound A) or its pharmacologically acceptable salt or its hydrate as an active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to N-hydroxy-
Leukocyte containing N- [6- (3-pyridylmethyl) -2H-1-benzopyran-3-ylmethyl] urea (hereinafter referred to as compound A) or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient The present invention relates to an infiltration inhibitor and an eosinophil infiltration inhibitor.

[0002]

2. Description of the Related Art In recent years, the role of leukocytes has been rapidly elucidated in various disease states, and it has become known to be involved in tissue disorders, dysfunctions and the like. Leukocyte infiltration can occur in various inflammation and allergic diseases, such as inflammation of the gastrointestinal system (especially inflammatory bowel disease and gastritis), skin diseases (especially psoriasis, eczema and dermatitis) and respiratory diseases (especially asthma, bronchial bronchi). Inflammation and allergic rhinitis, chronic obstructive respiratory disease),
It has been found to be involved in ischemic diseases, especially ischemia, reperfusion injury after ischemia and peripheral blood flow injury. In addition, various chemical mediators are produced at the inflammatory site where leukocyte infiltration is induced, and histamine, PA
F, leukotrienes, there are thromboxane A ₂ or the like. Among them, it was revealed that leukotrienes are produced by the action of 5-lipoxygenase from arachidonic acid, and that thromboxane A ₂ is produced after the action of cyclooxygenase by arachidonic acid.

[0003]

The present inventors have conducted various studies in view of the importance of the prevention and treatment of various inflammatory diseases. As a result, the inventors have found that the above-mentioned compound having both a lipoxygenase inhibitory action and a thromboxane converting enzyme inhibitory action. The present inventors have found that compound A further has a leukocyte infiltration inhibitory effect, and have completed the present invention. The present invention relates to N-hydroxy-N- [6- (3-pyridylmethyl) -2H-1-benzopyran-3-ylmethyl] urea (Compound A) or a pharmaceutically acceptable salt thereof or a hydrate thereof. The present invention relates to a leukocyte infiltration inhibitor and an eosinophil infiltration inhibitor as active ingredients.

[0004]

BEST MODE FOR CARRYING OUT THE INVENTION The pharmacologically acceptable salts of compound A used in the present invention include hydrochloric acid,
Salts of inorganic acids such as hydrobromic acid, sulfuric acid, bisulfite, phosphoric acid,
And salts of organic acids such as formic acid, acetic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, citric acid, gluconic acid, lactic acid, tartaric acid, methanesulfonic acid, and toluenesulfonic acid. Further, in the present invention, compound A
And hydrates of the salts thereof can also be used.

Compound A is generally administered orally. Preparations for oral administration can be prepared into powders, granules, tablets, capsules, syrups, emulsions, suspensions and the like. Other administration routes include injections (subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, etc.), instillations, and external preparations (nasal administration preparations, transdermal preparations, ointments, etc.) ), Suppositories (rectal suppositories, vaginal suppositories, etc.) and the like.

[0006] These preparations can be produced by a method known per se which is generally used in the preparation process. Hereinafter, a specific production method of the preparation will be described in detail.

[0007] Oral preparations include, as active ingredients, excipients (lactose, sucrose, starch, mannitol, crystallized cellulose, etc.), disintegrants (calcium carbonate, calcium carboxymethylcellulose, etc.), binders (gelatinized starch, arabic, etc.). Rubber, carboxymethylcellulose, polyvinylpyrrolidone, etc.) or lubricants (talc, magnesium stearate, polyethylene glycol 6000, etc.) are added and compression-molded. If necessary, masking of taste, enteric coating or persistence is known. It is manufactured by coating in the method described above.

[0008] Injectable preparations include active ingredients such as dispersants (Tween 80 (manufactured by Atlas Powder), HCO 60 (manufactured by Nikko Chemicals), polyethylene glycol, carboxymethylcellulose, sodium alginate, etc.), preservatives (methylparaben, propylparaben, etc.). Benzyl alcohol, etc.), isotonic agents (sodium chloride, glycerin, sorbitol, glucose etc.), etc., together with aqueous solvents (distilled water,
It is manufactured by dissolving, suspending or emulsifying in a physiological saline solution, Ringer's solution or the like or an oily solvent (olive oil, sesame oil, propylene glycol or the like).

[0009] An external preparation is produced by preparing the active ingredient into a solid, semi-solid or liquid composition. For example, in the solid composition, the active ingredient is added as it is, or excipients (lactose, mannitol, starch, etc.), thickeners (natural gums, cellulose derivatives, acrylic acid polymers, etc.) are added and mixed. It is manufactured by powdering. The liquid composition is produced in almost the same manner as in the case of injection. The semi-solid composition is preferably an aqueous or oily gel or an ointment. Any of these compositions may contain a pH adjuster, a preservative, and the like.

[0010] Suppositories are prepared by preparing the active ingredient as an oily or aqueous solid, semi-solid or liquid composition. Examples of the oil base used include glycerides of higher fatty acids, intermediate fatty acids, and vegetable oils. Examples of the aqueous base include polyethylene glycols and propylene glycol. As the aqueous gel base, for example, natural gums, cellulose derivatives,
Examples include vinyl polymers and acrylic acid polymers.

Compound A is a compound having not only a leukocyte infiltration inhibitory action and an eosinophil infiltration inhibitory action but also a lipoxygenase inhibitory action and a thromboxane converting enzyme inhibitory action. Therefore, by administering a drug (pharmaceutical composition) containing Compound A as an active ingredient, effects on various inflammatory diseases are expressed as additive or synergistic effects. For this reason, the dose of the medicament of the present invention may be lower than that of a medicament having only such an action alone. Since a sufficient effect can be obtained even with a small dose, it is expected that the side effects of each drug are also reduced.

The dose of Compound A can vary depending on the pathological condition, age, sex, body weight, administration time, dosage form, administration method, combination of other drugs, etc., of the patient to be administered. Generally speaking, in the case of oral drugs, the dose per adult is 5 to 1000 mg / day, preferably 5 to 100 mg.
In the case of an injection, the dose is 1 to 200 mg / day, preferably 1 to 20 mg / day. Compound A is administered once or several times a day in the above doses. Compound A had a NOAEL of 100 mg / kg or more in a 14-day repeated toxicity test in rats.

[0013]

The present invention will be described in more detail with reference to the following examples (formulation examples and test examples), but the scope of the present invention is not limited thereto.

Formulation Example 1 Preparation of Tablets Compound A 12.5 g Lactose 62.0 g Cornstarch 40.0 g Hydroxypropylcellulose 2.0 g Magnesium stearate 1.0 g After mixing the above compound A, lactose and cornstarch until uniform, hydroxypropylcellulose 5W
Add / V% ethanol solution, knead and granulate. After passing through a 16-mesh sieve and sieving, the tablets were compressed in a conventional manner to give tablets each having a weight of 130 mg, a diameter of 7 mm, and a main drug content of 25 mg.

Formulation Example 2 Preparation of Capsule Compound A 12.5 g Lactose 62.0 g Avicel 62.0 g Magnesium stearate 1.0 g The above compound A, lactose, Avicel PH-101 (manufactured by Asahi Kasei) and magnesium stearate are sufficiently added until uniform. After that, the mixture was filled into No. 3 capsules to give capsules having a content of 150 mg per capsule and a weight of the active ingredient of 25 mg.

Test Example 1 Drug Action of Guinea Pig on Antigen-Induced Leukocyte Infiltration Model Using a guinea pig sensitized by intramuscular administration of ovalbumin, a test compound suspended in 0.5% carboxymethylcellulose 1 hour before and 6 hours after antigen challenge was used. Oral administration. Antigen challenge was performed under mepyramine treatment, and 24 hours later, under anesthesia with pentobarbital, a polyethylene tube was sent to the airway, alveolar lavage was performed, and infiltrating cells were collected. The leukocyte count of the collected cells was measured and a painted sample was prepared. The number of eosinophils was measured under a mirror after staining the smeared sample with a staining solution, and the value obtained by calculating the ratio to other cells was multiplied by the total cell number. The control rate was calculated assuming that the number of eosinophils in the control group was 0% and the non-sensitized group was 100%. The test results are shown in Table 1.

[0017]

[Table 1]

[0018]

The compound A according to the present invention suppresses the production of thromboxanes and leukotrienes, which worsen the pathological condition in a disease site where arachidonic acid metabolism is active, suppresses leukocyte infiltration and eosinophils. Shows infiltration inhibitory action. For this reason, the present invention has been confirmed to have an effect on leukocyte infiltration inhibitory activity and eosinophil infiltration inhibitory effect. Various diseases, specifically, leukocyte infiltration inhibitor, eosinophil infiltration inhibitor, neutrophil Infiltration inhibitors, monocyte infiltration inhibitors, lymphocyte infiltration inhibitors. Prophylactic or therapeutic drugs for inflammation, antiallergic drugs, antiasthmatic drugs, dermatitis drugs, ulcer drugs, gastritis drugs, ulcerative colitis drugs, inflammatory bowel disease drugs, Crohn's disease drugs, cerebral blood flow It is useful as an improving drug, a brain tissue protective drug, a therapeutic agent for cerebrovascular disorders in the hyperacute, acute, subacute or chronic phase.

Continued on the front page F term (reference) 4C063 AA01 BB03 CC82 DD12 EE01 4C086 AA01 AA02 BC17 GA02 GA08 MA01 MA04 NA14 ZA51 ZB11

Claims (2)

[Claims] 1. N-hydroxy-N- [6- (3-pyridylmethyl) -2H-1-benzopyran-3-ylmethyl] urea (hereinafter referred to as compound A), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. A leukocyte infiltration inhibitor containing hydrate as an active ingredient. 2. An eosinophil infiltration inhibitor comprising Compound A or a pharmacologically acceptable salt thereof or a hydrate thereof as an active ingredient.